The invention relates to new piperidinyl-substituted pyridyl-alkane, alkene and alkine carboxamides with a saturated or one or several-fold unsaturated hydrocarbon residue in the carboxylic acid portion, methods for the synthesis of these compounds, medicaments containing these and their production as well as their therapeutic use especially as cytostatic agents and immunosuppresive agents, for example, in the treatment or prevention of various types of tumors and control of immune reactions, for example of autoimmune diseases.
A pressing need exists for new pharmaceuticals and/or medicaments for cytostatic and immunosuppressive therapy which not only possess a strong activity, but also exert diminished side effects in comparison to many classical cancerostatic agents. At the same time treatment of a broad as possible spectrum of tumors should be made accessible. Furthermore, effective cytostatic agents for an efficient therapy should be made available. Active ingredients of this type should also be exceptionally suitable in the mentioned indications for a combination therapy, be it in connection with other cytostatic agents or with radiation (for example X-rays, radioactive elements, such as cobalt, or linear accelerator, etc.), with operative procedures, heat treatment, etc.
Additionally, from another point of view, there exists a strong need in the field of tumor therapy for new compounds, for example for overcoming or avoiding resistances, which enrich the pallet of cancerostatics based on new modes of action in the ideal case.
This object was successfully solved by the creation of the piperidinyl-substituted pyridylalkane, alkene and alkine carboxamide derivatives as defined in detail in the claims and medicaments containing these as well as the use of these compounds, optionally in combination with other suitable active ingredients and adjuvants, for cytostatic and immunosuppressive therapy or prevention.
It is known that various pyridine compounds or substituted in a specific manner have pharmacologically useful properties; however, in contrast to the actions of the compounds according to the invention, these lie in completely different fields of indication.
Thus, xcfx89-pyridyl-alkane and/or alkene amides with anti-allergic activity are described in EP 0 210 782 which are referred to as having a 5-lipoxygenase-inhibiting and anti-histamine action, wherein the amide components of these compounds contain a piperizine or homopiperizine ring and the pyridine ring can be linked together in the 2-, 3- or 4-position. JP 63,179,869 describes further pyridyl amides, xcfx89-pyridylalkane and alkene amides as anti-allergic effective substances containing a substituted piperidine ring in the amine component. However, corresponding overlapping compound groups are excluded from the present claimed scope of protection according to the invention. Similarly compounds with the same properties are mentioned in Chem. Pharm. Bull 37, 100-105 (1989) and in J. Med. Chem. 1989, 583-593 whereby corresponding known substitutions are also excluded from the present scope of protection.
Pyridyl ureas, pyridyl thioureas and pyridyl carbonamides, wherein the amide portion is bound over an aryl-substituted alkyl chain with a piperidine ring or piperidine ring or piperazine ring, are described for example in EP-A-0 428 434 or in EP-A-0 512 902 as antagonists of the neurokinin receptor and substance P. Furthermore, pyridyl(alkyl)carbonamides, pyridyl(alkyl)sulfonamides and analogous ureas, wherein the pyridine ring is bound directly or over a methylene bridge with the amide group are disclosed in EP-A-0 479 601 as active ingredients with anti-arrhythmic properties.
Other structurally closely related compounds are represented by the piperidine compounds described in EP-A-0 330 026. These known compounds are distinguished by an anti-cholinesterase activity, an anti-amnesia activity as well as activities directed against hyperkinesia, senile dementia, mania and Alzheimer""s disease.
In WO 91/15 485, the production of pyridine-3,5-dicarboxylic acid esters and amides as well as their use for the treatment of tumor conditions is described. These compounds differ from the compounds according to the invention described below in very important structural features, for example by the dicarboxyl grouping on the pyridine ring or the absence of the hydrocarbon chain between the pyridine ring and the amide grouping. The compounds disclosed in WO 89/07 443 in the form of optically pure R(xe2x88x92)-niguldipin and further analogous dihydropyridines with cytotoxic activity have larger structural differences. However, as compared to these known compounds, the compounds according to the invention possess a higher activity and a wider spectrum of action despite the large structural differences.
In the international PCT patent applications WO 96/31477 or for example WO 96/31478 tricyclic anellated compounds are described which possess an anti-proliferative activity. All of these compounds described therein are distinguished in that they must imperatively possess a tricyclic anellated ring system with at least one nitrogen atom, for example 6, 11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridinyl ring system as a pharmaphoric group. The molecule portion at the other end of this tricyclic anellated system is uncommonly variable such that the pyridyl substitution given therein among numerous substitution possibilities merely represents one of many variation possibilities. A further meaningful difference in the substitution of these molecules in comparison to the compounds according to the invention is to be seen in the lack of the present structural element D (i.e. the inserted, optionally unsaturated hydrocarbon chain between the two essential terminal and/or opposite heterocycles); expressed in other words, the known compounds have a direct bond between the carboxy group and the piperidine ring.
A further essential difference of the compounds according to the invention in comparison to these known tricyclic anellated compounds is to be recognized in the presence of the terminal 3-pyridyl-substitution which must be present. The presence of this heterocyclic ring required according to the invention as well as this particular bond site in the substituted compounds according to the invention in comparison to the above mentioned anti-proliferative compounds of the state of the art with a tricyclic ring system is to be understood as a meaningful indication that, in a completely surprising manner, the pyridyl group is responsible for the anti-tumor action according to the invention.
In fact, the compounds according to the invention cover a different tumor spectrum from those named in the PCT/WO publications with this necessarily present tricyclic anellated ring system. In the mentioned PCT/WO publications of the state of the art, a treatment possibility in tumors is merely mentioned which is made in connection with a potential inhibition of the farnesyl protein transferase, whereby this mechanism relates to the expression of the activated rasoncogene. In contrast to this, the presently claimed new compounds with the 3-pyridyl-substitution required according to the invention are not limited to the therapy of tumor cells of this type with abnormal production of the ras-oncogene; rather, the therapy possibilities with the new compounds according to the invention extend to the combat of numerous other types of tumors with different causal mechanisms as well as immunosuppressive treatment possibilities such as autoimmune diseases.
In view of this art, the finding demonstrated in the pharmacological experimental section below according to which the compounds according to the general formula (I) with the particular substitutions defined below have superior pharmacological activities which make them particularly suitable in an excellent manner for the therapy of tumor illnesses over a broad anti-proliferative spectrum, was completely unexpected. The pharmacological finding that, aside from the cytostatic effectiveness, and the ability to inhibit abnormal cell growth especially with different tumor spectra, the compounds according to the invention also possess immunosuppressive properties and additionally favorable abortive properties without harmful mutagenic effects is to be considered as equally surprising.
Pyridyl compounds wherein, a non-aromatic heterocyclic ring with merely one ring nitrogen atom and optionally an additional ring oxygen atom, preferably a piperidinyl residue, is also incorporatedxe2x80x94however, in opposite orientationxe2x80x94as well as their use especially as cytostatic agents are subject matter of the older patent application P 196 24 704.7-44 which has not yet been published.
Therewith, the most important differentiating feature of the new compounds according to the invention with respect to these older, non-prepublished compounds is the orientation of the structural feature E which in the present application is always integrated in the opposite direction in the general formula (I). This novel construction of these structurally complicated compounds not only has an unexpected positive effect for the amenability of the synthesis, but also for the multiple variation possibilities of the structural element G found at the outer end of the molecule. As a result of this particular molecular structure now found, a novel class of compounds with, among others, pronounced cancerostatic effect is offered.
These new piperidinyl-substituted pyridyl carboxamides correspond to the following general formula: 
wherein the structural element E has the following meaning: 
and whereby the heterocyclic ring can optionally have a double bond and
n and p can be, independent from each other, 0, 1, 2 or 3 with the proviso that n+pxe2x89xa64, and whereby
q is 1; 2 or 3.
The substituent E can especially be present in the form of azetidine, pyrrolidine, piperidine, hexahydroazepine, octahydroazocine, morpholine, hexahydro-1,4-oxazepine and octahydro-1,4-oxacocine.
The meaning of the remaining substituents and the preferred embodiments of the compound groups according to the invention falling under the general formula as well as particularly preferred end products are defined in claims 1 to 7 in detail. In this connection, reference is also made to the substituent meanings which are illustrated as follows and are partially emphasized as preferred.
The compounds of Formula (I), which represent the end products can optionally exist as cis- and trans-isomers, E- and Z-isomers, for example when A is a cyclopropane ring or D contains one or more double bonds. Subject matter of the invention is the pure isomers as well as their mixtures.
Furthermore, the compounds of Formula (I) can contain one or more asymmetric carbon atoms and, as a result, exist in the form of different optical isomers (enantiomers, diastereomers). The invention includes all optical isomers and their racemic or non-racemic mixtures. Finally, compounds of Formula (I) can exist as endo/exo-isomers in case the ring system E is bicyclic. The pure endo- and exo-isomers as well as their mixtures are also comprised by the invention.
Compounds of Formula (I), in which G is a heterocyclic aromatic ring or contains such in an anellated ring system can optionally be present as tautomers when this heterocyclic ring is substituted by free hydroxy-, mercapto- or amino groups. In this case, the invention includes all tautomeric forms.
Subject matter of the invention are further pharmacologically acceptable acid addition salts of the compounds of Formula (I) with inorganic or organic acids. Preferable examples for addition salts with suitable inorganic acids are hydrochlorides, hydrobromides, hydroiodides, sulfates and phosphates. Addition salts of organic acids are preferably acetates, benzoates, citrates, fumarates, gluconates, malates, maleates, methanesulfonates, lactates, oxalates, succinates, tartrates and tosylates.
Compounds of Formula (I) as well as their acid addition salts can also be optionally present as hydrates or other solvates. The invention includes such hydrates and solvates.
In the compounds of Formula (I), the definitions for the atoms or atomic groups preferably have the following meanings:
Halogen means fluorine, chlorine, bromine or iodine;
Alkyl can be straight chained or branched and preferably signifies a C1-C6-alkyl residue, especially a methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, sec-butyl-, tert-butyl-, cyclopropylmethyl-, pentyl-, isopentyl-, tert-pentyl-, neopentyl-, cyclopropylethyl-, cyclobutylmethyl- or hexyl group.
Alkylene signifies for example methylene, ethylene, propylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene or decamethylene.
Alkenyl preferably signifies C3-C6-alkenyl and can be straight chained or branched and preferably signifies an allyl-, 2-butenyl-, 3-butenyl-, 2-methyl-2-propenyl-, 2-pentenyl-, 4-pentenyl-, 2-methyl-2-butenyl-, 3-methyl-2-butenyl-, 2-hexenyl-, 5-hexenyl-, 4-methyl-3-pentenyl- or 2,2-dimethyl-3-butenyl-group.
Alkenylene signifies for example ethenylene, propenylene, butenylene, pentenylene, hexenylene, hexadienylene, heptenylene, octenylene, nonenylene or decenylene.
Alkinyl preferably signifies C2-C6-alkinyl which can be straight chained or branched and can preferably signify an ethinyl-, propargyl-, 2-butinyl-, 3-butinyl-, 4-pentinyl-, 5-hexinyl- or 4-methyl-2-pentinyl group.
Alkinylene signifies for example propinylene, butinylene, pentinylene, hexinylene, hexeninylene, heptinylene, octinylene, noninylene or decinylene.
Cycloalkyl is preferably a C3-C8-cycloalkyl residue, especially a cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-, cycloheptyl- or cyclooctyl group.
Hydroxyalkyl contains a hydroxyl group in one of the above mentioned alkyl residues, especially in a C1-C6-alkyl residue, whereby among the C1-C6-hydroxyalkyl residues, the hydroxymethyl- and the hydroxyethyl residue are preferred.
Aside from the oxygen atom, alkoxy, preferably C1-C6 alkoxy, alkenyloxy, and alkinyloxy especially C1-C6 contain one of the above mentioned preferred C1-C6-alkyl-, C3-C6-alkenyl- and/or C3-C6-Alkinyl groups. Particularly preferred groups for this are the methoxy-, ethoxy-, isopropoxy-, tert-butoxy-, allyloxy- and propargyloxy groups.
Alkoxy, especially C1-C6-alkoxy, entirely or partially replaced by fluorine is for example difluoromethoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy.
Aside from the sulphur atom, alkylthio, alkenylthio, alkinyl-thio contain one of the above mentioned preferred C1-C6-alkyl-, C3-C6-alkenyl- or C3-C6-alkinyl groups. Preferred groups among these are the methylthio-, ethylthio-, isopropylthio- and tert-butylthio groups.
Cyclopentyloxy- and cyclopentylthio- and/or cyclohexyloxy- and cyclohexylthio residues represent preferred C3-C8-cycloalkyloxy and C3-C8-cycloalkylthio.
Aside from the oxygen atom, alkanoyloxy groups preferably contain an aliphatic acyl group with 1 to 7 carbon atoms. Among preferred alkanoyloxy groups are the acetoxy-, propionyloxy- and pivaloyloxy groups.
Alkoxycarbonyl groups, preferably C2-C7-alkoxycarbonyl groups contain, aside from the carbonyl group, one of the above mentioned alkoxy groups, especially C1-C6-alkoxy groups. Preferred alkoxycarbonyl groups are the methoxycarbonyl-, ethoxycarbonyl-, isopropoxycarbonyl-, isobutoxycarbonyl- and tert-butoxycarbonyl groups.
Aside from the oxygen atom, alkoxycarbonyloxy groups preferably contain one of the above mentioned C2-C7-alkoxy-carbonyl residues. Among preferred alkoxycarbonyl groups are the methoxycarbonyloxy-, ethoxycarbonyloxy-, isopropoxycarbonyloxy-, isobutoxycarbonyloxy- and tert-butoxycarbonyl groups as well as allyloxycarbonyloxy groups.
Aside from the carbonyl group, alkylaminocarbonyl, especially C2-C7-alkylaminocarbonyl and dialkylaminocarbonyl groups, preferably C3-C13-dialkylaminocarbonyl groups, contain an alkylamino- and/or dialkylamino residue whose alkyl groups correspond especially to the C1-C6-alkyl groups of the above description. Preferred groups are the dimethylaminocarbonyl-, diethylaminocarbonyl- and diisopropylamino-carbonyl groups.
Aside from the unsubstituted amino group, the amino groups of the Formula NR5R6 are one of the below mentioned alkylamino groups, especially C1-C6-alkylamino groups and/or dialkyl-amino groups, especially di-(C1-C6-alkyl)amino groups.
Alkylamino especially contains one of the above mentioned C1-C6-alkyl groups. Preferred groups are the methylamino-, ethylamino-, propylamino-, isopropylamino-, butylamino-, and the tert-butylamino groups.
The preferred di-(C1-C6-alkyl)amino residue carries two of the same or different of the above mentioned C1-C6-alkyl groups on the nitrogen atom. Preferred groups are the dimethylamino-, diethylamino-, dipropylamino-, diisopropylamino-, isopropyl-, methylamino-, dibutylamino- or tert-butylmethylamino groups.
Acyl, especially C1-C6-acyl, signifies the residue of an aliphatic saturated or unsaturated, straight chained, branched or cyclic carboxylic acid. Preferred acyl residues are formyl-, acetyl-, propionyl-, acryloyl-, butyryl-, isobutyryl-, methacryloyl-, cyclopropylcarbonyl-, pentanoyl-, pivaloyl-, cyclobutylcarbonyl-, hexanoyl- and dimethylacryloyl groups.
Alkanesulfonyl, especially C1-C6-alkanesulfonyl is preferably the methanesulfonyl-, ethanesulfonyl-, propanesulfonyl-, butanesulfonyl-, pentanesulfonyl- or hexanesulfonyl groups.
Saturated or unsaturated, preferably four- to eight-membered heterocycles with one or two hetero-atoms, are for example azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydropyridine, piperidine, tetrahydroazepine, hexahydroazepine, octahydroazocine, pyrazolidine, piperazine, morpholine, thiomorpholine, thiomorpholin-1,1-dioxide, hexahydrodiazepine or hexahydrooxazepine.
Preferred monocyclic aromatic five- or six-membered heterocycles with one to three hetero-atoms are for example furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl or triazinyl.
Anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring are preferably benzocyclobutyl, indanyl, indenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenylenyl, fluoroenyl, anthryl, dihydroanthryl, phenanthryl, dihydrophenanthryl, dihydrodibenzocycloheptenyl, tetrahydrobenzocycloheptenyl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl or tetrahydrodibenzocyclooctenyl. Their mono- or dioxo-derivates, i.e. for example the following rings: indanone, tetralone, anthrone, anthraquinone, fluoroenone, phenanthrone, dibenzocycloheptenone, dihydrodibenzocycloheptenone or tetrahydrodibenzocyclooctenone are also to be understood as partially hydrated carbocyclic ring systems.
Anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring are, for example, imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, isoindolinyl, bennzimidazolyl, indazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, thiazolopyridyl, isothiazolopyridyl, imidazopyridyl, pyrazolopyridyl, thienopyrimidinyl, chromanyl, benzopyranyl, quinolyl, isoquinolyl, dihydroquinolyl, tetrahydroquinolyl, benzodioxanyl, quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl, pyridoindolyl, acridinyl, phenanthridinyl, dihydrophenanthridinyl, dibenzoisoquinolinyl, dihydrodibenzoisoquinolinyl, phenothiazinyl, dihydrodibenzooxepinyl, benzocycloheptathienyl, dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, octahydrodibenzothiepinyl, dibenzoazepinyl, dihydrodibenzoazepnyl, octahydrodibenzoazepinyl, benzocycloheptapyridyl, dihydrobenzocycloheptapyridyl, pyridobenzoazepinyl, dihydropyridobenzoazepinyl, dihydropyridobenzodiazepinyl, dihydrodibenzoxazepinyl, dihydropyridobenzoxepinyl, dihydropyridobenzooxazepinyl, dihydrodibenzothiazepinyl or dihydropyridobenzothiazepinyl.
Furthermore, their mono- or dioxo-derivates and/or optionally their possible tautomers are also to be understood as partially hydrated heterocyclic ring systems, i.e. for example the residues of indolinone, isatin of benzoxazolone and/or its tautomer hydroxybenzoxazole, of benzisoxazolone, benzothiazolone, benzoisothiazolone and benzimidazolone and/or their corresponding tautomers hydroxybenzisoxazole, hydroxybenzothiazole, hydroxybenzoisothiazole and hydroxybenzimidazole, as well as indazolinone, of oxazolopyridinones, thiazolopyridinones, pyrazolopyridinones and imidazopyridinones and/or their corresponding tautomers hydroxyoxazolopyridine, hydroxythiazolopyridine, hydroxypyrazolopyridine and hydroxyimidazopyridine, the residues for the series chromanone, chromone, quinolinone, dihydroquinolinone, tetrahydrocarbazolone, acridone, phenannthridone, benzoisoquinolone, dihydrodibenzooxepinones, benzocycloheptathiophenones, dihydrothienobenzothiepinones, dihydrodibenzothiepinones, dihydrodibenzoazepinones, benzocycloheptapyridinones, dihydropyridobenzoazepinones, dihydropyridobenzodiazepinones/dihydropyridobenzoxazeninones, dihydrodibenzothiazepinones and of dihydropyridobenzothiazepinones.
Saturated and unsaturated monocyclic, four- to eight-membered heterocycles (as the group xe2x80x94NR13R15) which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from N and/or S and/or O, are for example azetidine, pyrrolidine, piperidine, (1H)-tetrahydropyridine, hexahydroazepine, (1H)-tetrahydroazepine,. octahydroazocine. pyrazolidine, piperazine, hexahydrodiazepine, morpholine, hexahydroxazepine, thiomorpholine or thiomorpholin-1,1-dioxide.
Saturated or unsaturated bi- or tricyclic, anellated or bridged heterocycles with 8 to 16 ring atoms, (in the form of the group xe2x80x94NR13R15) which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms, selected from N and/or S and/or O, are for example 5-aza-bicyclo[2.1.1]hexane, 2-aza-bicyclo[2.2.1]heptane, 7-aza-bicyclo[2.2.1]heptane, 2,5-diaza-bicyclo[2.2.1]heptane, 2-aza-bicyclo[2.2.2]octane, 8-aza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.2]octane, 9-aza-bicyclo[3.3.1]nonane, indoline, isoindoline, (1H)-dihydroquinoline, (1H)-tetrahydroquinoline, (2H)-tetrahydroisoquinoline, (1H)-tetrahydroquinoxaline, (4H)-dihydrobenzoxazine, (4H)-dihydrobenothiazine, (1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[c]azepine, (1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine, (5H)-tetrahydrobenzo[b]thiazepine, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, (10H)-dihydroacridine, (10H)-dihydrophenanthridine, 1,2,3,4-tetrahydroacridanone, (10H)-phenoxazine, (10H)-phenothiazine, (5H)-dibenzazepine, (5H)-dihydrodibenzazepine, (5H)-octahydrodibenzazepine, dihydrobenzo[d,e]isoquinoline, (5H)-dihydrodibenzodiazepine, (5H)-benzo[b]pyrido[f]azepine, (5H)-dihydrobenzo[b]pyrido-[f]azepine (11H)-dihydrodibenzo[b,e]oxazepine, (11H)-dihydrodibenzo[b,e]thiazepine, (10H)-dihydrodibenzo[b,f]oxazepine, (10H)-dihydrodibenzo[b,f]thiazepine, (5H)-tetrahydrodibenzazocine, (11H)-dihydrobenzo[e]pyrido[b]-1,4-diazepin-6-one, (11H)-dihydrobenzo[b]pyrido[e]-1,4-diazepin-5-one.
Spirocyclic ring system (in the form of the group ER13, R15), comprising the residue E and a C3-C8-cycloalkane ring, are for example 2-azaspiro[3,4]octane, or the residue 2-azaspirononanes, azaspirodecanes and azaspiroundecanes.
Spirocyclic ring systems (in the form of the group ER13, R15), comprising the residue E and a saturated four to seven-membered heterocycle with one or two hetero-atoms respectively are for example 5,8-dioxa-2-aza-spiro[3,4]octane or a residue from the series of dioxaazaspirononanes, dithiaazaspirononanes, oxadiazaspirononanes, triazaspirononanes, diazaspirodecanes, dioxaazaspirodecanes, dithiaazaspirodecanes, oxadiazaspirodecanes, triazaspirodecanes, dioxaazaspiroundecanes, dithiaazaspiroundecanes, oxadiazaspiroundecanes or triazaspiroundecanes as well as their mono- and dioxo derivates.
Spirocyclic ring systems (in the form of the group ER13R15), comprising the residue E and an anellated, bi- or tricyclic, partially hydrated carbocyclic or heterocyclic ring system are preferably spiro[indan-piperidines], spiro[piperidin-tetrahydronaphthalines], spiro[benzodioxol-pyrrolidines], spiro[benzodioxol-piperidines], spiro[benzodioxol-hexahydroazepines], spiro[benzo-1,3-dioxin-piperidines], spiro[dihydrobenzo-1,3-oxazin-piperidines], spiro[oxodihydrobenz-1,3-oxazin-piperidines] and spiro[piperidin-oxo-1,2,3,4-tetrahydrochinazolines].
Very particularly preferred embodiments of the invention are represented by the following end products:
N-[4-(4-phenyl-piperidin-1-yl)-butyl]-3-pyridin-3-yl-acrylamide;
N-{4-[4-(1H-indol-3-yl)-piperidin-1-yl]-butyl}-3-pyridin-3-yl-acrylamide;
N-{4-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-butyl}-3-pyridin-3-yl-acrylamide;
N-[4-(4-benzotriazol-1-yl-piperidin-1-yl)-butyl]-3-pyridin-3-yl-acrylamide;
N-{4-[4-(hydroxy-diphenylmethyl)-piperidin-1-yl]-butyl}-2-(pyridin-3-yloxy)-acetamide;
N-[4-(4,4-diphenyl-piperidin-1-yl)-butyl]-3-pyridin-3-yl-acrylamide;
N-{4-[4-(6,11-dihydro-dibenzo[b,e]thiepin-11-yliden)-piperidin-1-yl]-butyl}-3-pyridin-3-yl-propionamide dihydrochloride/semi-isopropanol;
N-{4-[4-(6,11-dihydro-dibenzo[b,e]thiepin-11-yliden)-piperidin-1-yl]-butyl}-5-pyridin-3-yl-pentanamide;
N-{4-[4-(4,9-dihydro-thieno[2,3-b]-benzo[e]thiepin-4-yliden)-piperidin-1-yl]-butyl}-3-pyridin-3-yl-propionamide;
N-{4-[4-(4,9-dihydro-thieno[2,3-b]-benzo[e]thiepin-4-yliden)-piperidin-1-yl]-butyl}-3-pyridin-3-yl-acrylamide;
N-[4-(4-diphenylphosphinoyloxy-piperidin-1-yl)-butyl]-3-pyridin-3-yl-acrylamide;
N-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-butyl]-3-pyridin-3-yl-acrylamide.
Concretely, the invention relates to new compounds of the general Formula (I) 
wherein
R1 is selected from hydrogen, hydroxy, halogen, cyano, carboxy; saturated, single or several-fold unsaturated, branched or straight chained or cyclic hydrocarbon residues such as alkyl, alkenyl, alkinyl or cycloalkyl; trifluoromethyl or hydroxyalkyl;
aryl such as phenyl or heteroaryl such as pyridyl;
alkoxy, cycloalkyloxy, alkenyloxy, alkinyloxy or aralkyloxy such as the benzyloxy group, alkoxycarbonyl; aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyloxy, alkoxycarbonyloxy; alkylthio, cycloalkylthio, alkenylthio, alkinylthio; aryloxy such as phenoxy, heteroaryloxy such as pyridyloxy, heteroarylthio such as pyridylthio, and NR5R6, whereby
R5 and R6 are selected independent of each other from hydrogen, saturated or unsaturated hydrocarbon residues such as alkyl, alkenyl, alkinyl, or aryl such as phenyl and aralkyl such as benzyl;
R2 is selected from hydrogen, halogen, cyano, saturated hydrocarbon residues such as alkyl, or halogenated hydrocarbon residues such as trifluoromethyl, hydroxy, alkoxy, aralkyloxy residues such as benzyloxy, as well as alkanoyloxy,
whereby R1 and R2, in the case that they are immediately adjacent to each other, optionally form a bridge which is selected from
xe2x80x94(CH2)4xe2x80x94 and xe2x80x94(CHxe2x95x90CH)2xe2x80x94 and xe2x80x94CH2O xe2x80x94CR7R8xe2x80x94Cxe2x80x94, wherein
R7 and R8 are selected independently of each other from hydrogen and alkyl residues;
R3 is selected from hydrogen, halogen, saturated hydrocarbon residues such as alkyl, or halogenated hydrocarbon residues such as trifluoromethyl, or hydroxyalkyl;
R4 is selected from hydrogen, hydroxy, saturated, single or several-fold unsaturated, branched or straight chained or cyclic hydrocarbon residues such as alkyl, alkenyl, alkinyl or cycloalkyl, alkoxy and aralkyloxy such as benzyloxy;
k is 0 or 1;
A is selected from alkylene with at least 2 carbon atoms which is optionally substituted one to three-fold by straight chained or branched chained hydrocarbon residues such as alkyl, hydroxy, alkoxy, halogen such as fluorine, or aryl such as phenyl,
alkylene with at least 2 carbon atoms, wherein a methylene unit is isosterically replaced by O, S, NR9, CO, SO or SO2 whereby, with the exception of CO, the isosteric substitution cannot be adjacent to the amide group and, in NR9, the residue R9 is selected from hydrogen, alkyl, alkenyl, alkinyl, acyl or alkanesulfonyl;
cycloalkylene such as 1,2-cyclopropylene;
alkenylene with at least 2 carbon atoms which is optionally substituted one to three-fold by alkyl, hydroxy, alkoxy, fluorine, cyano or aryl such as phenyl;
kadienylene with at least 4 carbon atoms, which is optionally substituted once or twice by alkyl, fluorine, cyano or aryl such as phenyl;
1,3,5-hexatrienylene, which is optionally substituted by alkyl, fluorine, cyano or aryl such as phenyl; as well as
ethinylene;
D is selected from alkylene with at least 2 carbon atoms, which is optionally substituted once or twice by alkyl, hydroxy, or alkoxy; alkenylene with at least 4 carbon atoms, which is optionally substituted once or twice by alkyl, hydroxy, or alkoxy;
alkinylene with at least 4 carbon atoms, which is optionally substituted once or twice by alkyl, hydroxy, or alkoxy; as well as
alkylene, alkenylene or alkinylene with at least 2 or 4 carbon atoms respectively, wherein one to three methylene units is each isosterically replaced by O, S, NR10, CO, SO or SO2, wherein
R10 has the same meaning as R9 but is selected independently thereof;
E is selected from 
xe2x80x83whereby the heterocyclic ring can optionally have a double bond and
n and p can be, independent of each other, 0, 1, 2 or 3 with the proviso that n+pxe2x89xa64.
q is 1, 2 or 3;
R11 is selected from hydrogen, alkyl, hydroxy, hydroxymethyl, carboxy, or alkoxycarbonyl with at least 2carbon atoms and
R12 is selected from hydrogen, alkyl or an oxo group adjacent to a nitrogen atom or
R11 and R12, optionally together, form a C1-C3-alkylene bridge under formation of a bicyclic ring system;
G is selected from G1, G2, G3, G4 or G5, wherein
G1 is the residue
xe2x80x94(CH2)rxe2x80x94(CR14R15)sxe2x80x94R13xe2x80x83xe2x80x83(G1)
xe2x80x83and
r is a number from 0 to 3, and
s is 0 or 1;
R13 is selected from hydrogen, alkyl, or alkenyl, alkinyl, cycloalkyl with at least 3 carbon atoms in the saturated or cyclic residues;
saturated or unsaturated, four to seven-membered heterocycles which can contain one or two hetero-atoms selected from N and/or S and/or O;
benzyl, phenyl;
monocyclic aromatic five- or six-membered heterocycles which can contain 1 to 3 hetero-atoms selected from N and/or S and/or O and are either directly bound or bound over a methelyene group;
anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 18, preferably up to 16 ring atoms, and at least one aromatic ring, whereby the bond can occur either over an aromatic or a hydrated ring and either directly or over a methylene group;
anellated bi- and tricyclic aromatic or.partially hydrated heterocyclic ring systems with 8 to 18, preferably up to 16 ring atoms, and at least one aromatic ring, whereby one to three ring atoms can be selected from N and/or S and/or O and the bond can occur either over an aromatic or a hydrated ring and either directly or over a methylene group;
R14 has the same meaning as R13 but is selected independently thereof;
R15 is selected from hydrogen, hydroxy, methyl, benzyl, phenyl; monocyclic aromatic five or six-membered heterocycles, which can contain one to three hetero-atoms selected from the group N and/or S and/or O and are either bound directly or over a methylene group;
anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 18, preferably up to 16 ring atoms, and at least one aromatic ring, wherein the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group;
anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 18, preferably up to 16 ring atoms, and at least one.aromatic ring, wherein one to three ring atoms can be selected from N and/or S and/or O and the linkage can occur either over an aromatic ring or a hydrated ring and either directly or over a methylene group;
G2 has the meaning
xe2x95x90(C)uR13R15xe2x80x83xe2x80x83(G2),
xe2x80x83whereby
R13 and R15 have the above meaning and
u represents the number 0 or 1, or signifies the residue
xe2x95x90CR13R15
xe2x80x83which is sound by means of a double bond to E in the case that u=1, or can signify a ring system bound over the carbon atom selected from cycloalkyl with at least 3 carbon atoms; saturated, four to seven-membered heterocycles which can contain one or two hetero-atoms selected from N and/or S and/or O;
anellated bi- and tricyclic partially hydrated carboxocyclic ring system with 8 to 18, preferably up to 16 ring atoms, and at least one aromatic ring;
anellated bi- and tricyclic partially hydrated heterocyclic ring systems with 8 to 18, preferably up to 16 ring atoms, and at least one aromatic ring, wherein one to three ring atoms can be selected from N and/or S and/or O;
or, in the case that u=0, the two germinal substituents R13 and R15 can form a spirocycle together with the bonding atom of the ring E selected from cycloalkyl,
saturated, four to seven-membered heterocycles which can contain one or two hetero-atoms selected from N and/or S and/or O;
anellated bi- and tricyclic partially hydrated carbocyclic ring systems with 8 to 18, preferably 16 ring atoms, and at least one aromatic ring;
anellated bi- and tricyclic partially hydrated heterocyclic ring systems with 8 to 18, preferably up to 16 ring atoms, and at least one aromatic ring, whereby 1 to 3 ring atoms can be selected from N and/or S and/or O;
G3 is selected from 
xe2x80x83whereby r and s as well as the substituents R13, R14 and R15 can have the above meanings, or the grouping
xe2x80x94NR13R15
xe2x80x83can also be a nitrogen heterocycle bound over the nitrogen atom selected from saturated or unsaturated monocyclic, four to eight-heterocycles which, aside from the essential nitrogen atom, can optionally further contain one or two further hetero-atoms selected from N and/or S and/or O, or saturated or unsaturated bi- or tricyclic, anellated or bridged heterocycles with 8 to 18, preferably up to 16 ring atoms, which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from N and/or S and/or O;
G4 is selected from 
xe2x80x83whereby r and s as well as the substituents R13, R14 and R15 can have the above meanings and
R16 has the same meanings as R5 but is selected independently thereof,
R17 is selected from trifluoromethyl, alkoxy, alkenyloxy with at least 3 carbon atoms; or benzyloxy; and
Ar1 and Ar2 are selected independently from each other from phenyl, pyridyl or naphthyl;
G5 has the meaning
xe2x80x94Wxe2x80x94(CH2)rxe2x80x94(CR14R15)sxe2x80x94R13xe2x80x83xe2x80x83(G5a)
xe2x80x83or 
xe2x80x83whereby r and s as well as the substitutents R13, R14, R15, Ar1 and Ar2 can have the above meanings and
W is O or S,
xe2x80x83whereby the ring systems xe2x95x90CR13R15, xe2x80x94NR13R15 and optionally ER13, R15 as well as aromatic ring systems in the substituents R1, R2, R4, R5, R6, R13, R14, R15, R16, R17, Ar1 and Ar2 can be substituted independently from each other by one to three of the same or different groups selected from halogen, cyano, alkyl, trifluoromethyl, cycloalkyl with at least 3 carbon atoms, phenyl, benzyl, hydroxy, hydroxyalkyl, alkoxy, alkoxy entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, alkylthio, carboxy, carboxyalkyl, carboxyalkenyl with at least 2 carbon atoms or alkoxycarbonyl with at least 2 carbon atoms, benzyl-oxycarbonyl, nitro, amino, monoalkylamino, dialkylamino and, for two adjacent residues on the aromatic ring, methylenedioxy, and whereby alkyl-, alkenyl- and cycloalkyl residues in the groups G1 to G5 can be substituted by one or two of the same or different groups selected from hydroxy, carboxy, alkoxycarbonyl with at least 2 carbon atoms, benzyloxycarbonyl, amino, monoalkylamino and dialkylamino, whereby
G cannot signify the residue xe2x80x94CHR14xe2x80x94R13 or xe2x80x94C(OH)R14xe2x80x94R13 or xe2x95x90CR13R15 or xe2x80x94Oxe2x80x94CHR14xe2x80x94R13 in the case when simultaneously
R13 is hydrogen, alkyl or phenyl optionally substituted by halogen, alkyl, hydroxy, alkoxy or trifluoromethyl
R14 and/or R15 is pyridyl or phenyl optionally substituted with halogen, alkyl, hydroxy, alkoxy or trifluoromethyl,
A is alkylene, optionally substituted ethenylene or butadienylene,
D is alkylene and
E is piperidine substituted in the 4-position;
the cis- and trans-isomers, E- and Z-isomers of the above defined compounds, especially in case that A is a cyclopropane ring or D contains one or more double bonds, including the enantiomers, diastereomers and other isomers of the above defined compounds as well as their racemic or non-racemic mixtures as well as the pure endo- and/or exo-isomers of the above defined compounds as well as their mixtures;
the respective tautomeric compounds;
and the acid addition salts of the above defined compounds including their hydrates and solvates.
According to a further embodiment of the invention, the new, pyridylalkane, pyridylalkene and pyridylalkine acid amide compounds correspond with respect to their substitutions formula (I) 
wherein
R1 is selected from hydrogen, halogen, cyano, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, trifluoromethyl, C3-C8-cycloalkyl, C1-C6-hydroxyalkyl, hydroxy, C1-C6-alkoxy, C3-C6-alkenyloxy, C3-C6-alkinyloxy, benzyloxy, C1-C7-alkanoyloxy, C2-C7-alkoxycarbonyloxy, C1-C6-alkylthio, C3-C6-alkenylthio, C3-C6-alkinylthio, C3-C8-cycloalkyloxy, C3-C8-cycloalkylthio, C2-C7-alkoxycarbonyl, aminocarbonyl, C2-C7-alkylaminocarbonyl, C3-C13-dialkylaminocarbonyl, carboxy, phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio, and NR5R6, wherein
R5 and R6 are selected independently of each other from hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, benzyl and phenyl;
R2 is selected from hydrogen, halogen, cyano, C1-C6-alkyl, trifluoromethyl, hydroxy, C1-C6-alkoxy, benzyloxy and C1-C7-alkanoyloxy; R1 and R2, if adjacent, optionally form a bridge selected from xe2x80x94(CH2)4xe2x80x94 and xe2x80x94(CHxe2x95x90CH)2xe2x80x94 or xe2x80x94CH2Oxe2x80x94CR7R8xe2x80x94Oxe2x80x94, wherein
R7 and R8 are selected independently from each other from hydrogen and C1-C6-alkyl;
R3 is selected from hydrogen, halogen, C1-C6-alkyl, trifluoromethyl and C1-C6-hydroxyalkyl;
R4 is selected from hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C3-C6-cycloalkyl, hydroxy, C1-C6-alkoxy and benzyloxy;
k is 0 or 1,
A is selected from
C1-C6-alkylene, optionally substituted one to three-fold by C1-C3-alkyl, hydroxy, C1-C3-alkoxy, fluorine, or phenyl,
C2-C6-alkylene, in which a methylene unit is isosterically replaced by O, S, NR9, CO, SO or SO2, whereby, with the exception of CO, the isosteric substitution cannot be adjacent to the amide group and R9 is selected from hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C1-C6-acyl or C1-C6-alkanesulfonyl,
1,2-cyclopropylene,
C2-C6-Alkenylene, optionally substituted once to three-fold by C1-C3-alkyl, hydroxy, C1-C3-alkoxy, fluorine, cyano or phenyl,
C4-C6-alkadienylene, optionally substituted once or twice by C1-C3-alkyl, fluorine, cyano or phenyl;
1,3,5-hexatrienylene, optionally substituted by C1-C3-alkyl, fluorine, cyano or phenyl, and
ethinylene
D is selected from C2-C10-alkylene, optionally substituted once or twice by C1-C6-alkyl, hydroxy, or C1-C6-alkoxy;
C4-C10-alkenylene, optionally substituted once or twice by C1-C6-alkyl, hydroxy, or C1-C6-alkoxy;
C4-C10-alkinylene, optionally substituted once or twice by C1-C6-alkyl, hydroxy, or C1-C6-alkoxy; and
C2-C10-alkylene, C4-C10-alkenylene or C4-C10-alkinylene, in which one to three methylene units are isosterically replaced by O, S, NR10, CO, SO or SO2, whereby R10 has the same meaning as R9, but is selected independently thereof;
E is selected from 
xe2x80x83whereby the heterocyclic ring can optionally have a double bond and
n and p can be, independent of each other, 0, 1, 2 or 3 with the proviso that n+pxe2x89xa64, wherein
q is 1,2 or 3;
R11 is selected from hydrogen, C1-C6-alkyl, hydroxy, hydroxymethyl, carboxy, or C2 C7-alkoxycarbonyl and
R12 is selected from hydrogen, C1-C6-alkyl or an oxo group adjacent to a nitrogen atom,
R11 and R12 optionally together, form a C1-C3-alkylene bridge under formation of a bicyclic ring system;
G is selected from G1, G2, G3, G4 or G5, whereby
G1 is xe2x80x94(CH2)rxe2x80x94(CR14R15)sxe2x80x94R13 (G1)
r is a number from 0 to 3,
s is 0 or 1 and
R13 is selected from
hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C3-C8-cycloalkyl;
saturated or unsaturated, four to seven-membered heterocycles, which can contain one or two hetero-atoms selected from N and/or S and/or O;
benzyl, phenyl;
monocyclic aromatic five or six-membered heterocycles, which can contain one to three hetero-atoms selected from N and/or S and/or O and are either bound directly or over a methylene group, anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group, anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms can be selected from N and/or S and/or O and the linkage can occur either over an aromatic ring or a hydrated ring and either directly or over a methylene group,
R14 has the same meaning as R13, but is selected independently thereof;
R15 is selected from hydrogen, hydroxy, methyl, benzyl, phenyl; monocyclic aromatic five or six-membered heterocycles, which can contain one to three hetero-atoms selected from N and/or S and/or O and are either bound directly or over a methylene group, anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring wherein the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group, anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms can be selected from N and/or S and/or O and the linkage can occur either over an aromatic ring or a hydrated ring and either directly or over a methylene group,
G2 is
xe2x95x90(C)uR13R15xe2x80x83xe2x80x83(G2),
xe2x80x83whereby
R13 and R15 have the above meaning and
u represents the number 0 to 1, or signifies the residue
xe2x95x90CR13R15
xe2x80x83which is bound by means of a double bond to E in the case that u=1, or can signify a ring system bound over the carbon atom.selected from C3-C8-cycloalkyl;
saturated, four to seven-membered heterocycles which can contain one or two hetero-atoms selected from N and/or S and/or O;
anellated bi- and tricyclic partially hydrated carboxocyclic ring system with 8 to 16 ring atoms and at least one aromatic ring;
anellated bi- and tricyclic partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms can be selected from N and/or S and/or O;
or, in the case that u=0, the two germinal substituents R13 and R15 can form a spirocycle together with the bonding atom of the ring E selected from cycloalkyl, saturated, four to seven-membered heterocycles which can contain one or two hetero-atoms selected from N and/or S and/or O;
anellated bi- and tricyclic partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring;
anellated bi- and tricyclic partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, whereby 1 to 3 ring atoms can be selected from N and/or S and/or O;
G3 is selected from 
xe2x80x83whereby r and s as well as the substituents R13, R14 and R15 can have the above meanings, or the grouping
xe2x80x94NR13R15
can also be a nitrogen heterocycle bound over the nitrogen atom selected from saturated or unsaturated monocyclic, four to eight-membered heterocycles which, aside from the essential nitrogen atom, can optionally further contain one or two further hetero-atoms selected from N and/or S and/or O, or saturated or unsaturated bi- or tricyclic, anellated or bridged heterocycles with 8 to 16 ring atoms, which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from N and/or S and/or O;
G4 is selected from 
xe2x80x83whereby r and s as well as the substituents R13, R14 and R15 can have the above meanings and
R16 has the same meanings as R5, but is selected independently thereof,
R17 is selected from trifluoromethyl, C1-C6-alkoxy, C3-C6-alkenyloxy and benzyoxy; and
Ar1 and Ar2, are selected independently from each other from phenyl, pyridyl or naphthyl;
G5 has the meaning
xe2x80x94Wxe2x80x94(CH2)rxe2x80x94(CR14R15)sxe2x80x94R13xe2x80x83xe2x80x83(G5a)
xe2x80x83or 
xe2x80x83whereby r and s as well as the substitutents R13, R14, R15, Ar1 and Ar2 can have the above meanings and
W is O or S,
whereby the ring systems xe2x95x90CR13R15, xe2x80x94NR13R15 and optionally ER13, R15 as well as aromatic ring systems in the substituents R1, R2, R4, R5, R6, R13, R14, R15, R16, R17, Ar1 and Ar2 can be substituted independently from each other by one to three of the same or different groups selected from halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-cycloalkyl, phenyl, benzyl, hydroxy, C1-C6-hydroxyalkyl, C1-C6-alkoxy, C1-C6-alkoxy entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, C1-C6-alkylthio, carboxy, C2-C7-carboxyalkyl, C2-C7-carboxyalkenyl, C2-C7-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C1-C6-alkylamino, di-(C1-C6-alkyl)amino and, for two adjacent residues on the aromatic ring, methylenedioxy, and whereby
alkyl-, alkenyl- and cycloalkyl residues in the groups G1 to G5 can be substituted by one or two of the same or different groups selected from hydroxy, carboxy, C2-C7-alkoxycarbonyl, benzyloxycarbonyl, amino, mono-C1-C6-alkylamino and di-(C1-C6-alkyl)amino, whereby
G cannot signify the residue xe2x80x94CHR14xe2x80x94R13 or xe2x80x94C(OH)R14xe2x80x94R13 or xe2x95x90CR13R15 or xe2x80x94Oxe2x80x94CHR14xe2x80x94R13 in the case when simultaneously
R13 is hydrogen, alkyl or phenyl (optionally substituted by halogen, alkyl, hydroxy, alkoxy or trifluoromethyl)
R14 and/or R15 is pyridyl or phenyl optionally substituted with halogen, alkyl, hydroxy, alkoxy or trifluoromethyl,
A is alkylene, optionally substituted ethenylene or butadienylene,
D is alkylene and
E is piperidine substituted in the 4-position;
the cis- and trans-isomers, E- and Z-isomers of the respective above defined compounds, especially in case that A is a cyclopropane ring or D contains one or more double bonds, including the enantiomers, diastereomers and other isomers of the respective above defined compounds as well as their racemic or non-racemic mixtures, the pure endo- and exo-isomers of these compounds as well as their mixtures;
their respective tautomers compounds as well as
the corresponding acid addition salts including their hydrates and solvates.
According to a preferred embodiment, the invention relates to compounds of the general Formula (I), 
wherein
R1 is selected from hydrogen, halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-cycloalkyl, C1-C-hydroxyalkyl, hydroxy, C1-C4-alkoxy, benzyloxy, C1-C4-alkylthio, C1-C5-alkanoyloxy, C1-C4-alkylthio, C2-C5-alkoxycarbonyl, aminocarbonyl, C2-C5-alkylaminocarbonyl, C3-C9-dialkylaminocarbonyl, carboxy, phenyl, phenoxy, phenylthio, pyridyloxy, and NR5R6, whereby
R5 and R6 are selected independently from each other from hydrogen and C1-C6-alkyl;
R2 is selected from hydrogen, halogen, cyano, C1-C6-alkyl, trifluoromethyl, hydroxy, C1-C4-alkoxy;
R3 is selected from hydrogen, halogen and C1-C6-alkyl;
R4 is selected from hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-cycloalkyl, hydroxy, C1-C6-alkoxy and benzyloxy;
k is 0 or 1,
A is selected from C2-C6-alkylene, optionally substituted one to three-fold by C1-C3-alkyl, hydroxy, fluorine, or phenyl,
C2-C6-alkylene, in which a methylene unit is isosterically replaced by O, S, NR9, CO or SO2, whereby, with the exception of CO, the isosteric substitution cannot be adjacent to the amide group and R9 is selected from hydrogen, C1-C6-alkyl, C1-C6-acyl or methanesulfonyl;
1,2-cyclopropylene,
C2-C6-Alkenylene, optionally substituted once to three-fold by C1-C3-alkyl, hydroxy, fluorine, cyano or phenyl,
C4-C6-alkadienylene, optionally substituted once to twice by C1-C3-alkyl, fluorine, cyano or phenyl;
1,3,5-hexatrienylene, optionally substituted by C1-C3-alkyl, fluorine, cyano, and
ethinylene
D is selected from C2-C10-alkylene, optionally substituted once or twice by C1-C3-alkyl or hydroxy;
C4-C10-alkenylene, optionally substituted once or twice by C1-C3-alkyl or hydroxy;
C4-C10-alkinylene, optionally substituted once or twice by C1-C3-alkyl or hydroxy; as well as
C2-C10-alkylene, C4-C10-alkenylene or C4-C10-alkinylene, in which one to three methylene units are isosterically replaced by O, S, NR10, CO, SO or SO2, whereby
R10 has the same meaning as R9, but is selected independently thereof;
E is selected from 
xe2x80x83whereby the heterocyclic ring can optionally have a double bond and
n and p can be, independent of each other, 0, 1, 2 or 3 with the proviso that n+pxe2x89xa64, and
q is one or 2;
R11 is selected from hydrogen, C1-C3-alkyl, hydroxy, hydroxymethyl, carboxy, or C2-C7-alkoxycarbonyl and
R12 is selected from hydrogen or an oxo group adjacent to a nitrogen atom or
R1l and R12, optionally together, form a C1-C3-alkylene bridge under formation of a bicyclic ring system;
G is selected from G1, G2, G3, G4 or G5, whereby
G1 is
xe2x80x94(CH2)rxe2x80x94(CR14R15)sxe2x80x94R13xe2x80x83xe2x80x83(G1)
xe2x80x83whereby
r signifies the number 0 to 2,
s signifies the number 0 or 1 and
R13 is selected from
hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C3-C8-cycloalkyl;
benzyl, phenyl;
monocyclic aromatic five or six-membered heterocycles, which can contain one to three hetero-atoms selected from N and/or S and/or O and are either bound directly or over a methylene group, anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group, anellated bi- and tricyclic aromatic or partially hydrated heterocyclic,ring systems with 8 to 16 ring atoms and at least.one aromatic ring, wherein one to three ring atoms can be selected from N and/or S and/or O and the linkage can occur either over an aromatic ring or a hydrated ring and either directly or over a methylene group,
R14 has the same meaning as R13, but is selected independently thereof;
R15 is selected from hydrogen, hydroxy, methyl, benzyl, phenyl; monocyclic aromatic five or.six-membered heterocycles, which can contain one to three hetero-atoms selected from N and/or S and/or C and are either bound directly or over a methylene group, anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group, anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms can be selected from N and/or S and/or O and the linkage can occur either over an aromatic ring or a hydrated ring and either directly or over a methylene group;
G2 is
xe2x95x90(C)uR13R15xe2x80x83xe2x80x83(G2),
xe2x80x83whereby
R13 and R15 have the above meanings and
u is the number 0 or 1,
or the grouping
xe2x95x90CR13R15
xe2x80x83which is bound by means of a double bond to E in the case that u=1 can also be a ring system bound over the carbon atom selected from anellated bi- and tricyclic partially hydrated carboxocyclic ring system with 8 to 16 ring atoms, and at least one aromatic ring;
anellated bi- and tricyclic partially hydrated heterocyclic ring systems with 8 to 16 ring atoms, and at least one aromatic ring, wherein one to three ring atoms can be selected from N and/or S and/or O;
or, in the case that u=0, the two germinal substituents R13 and R15 can form a spirocycle together with the bonding atom of the ring E selected from saturated, four to seven-membered heterocycles which can contain one or two hetero-atoms selected from N and/or S and/or O;
anellated bi- and tricyclic partially hydrated carbocyclic ring systems with 8 to 16 ring atoms, and at least one aromatic ring;
anellated bi- and tricyclic partially hydrated heterocyclic ring systems with 8 to 16 ring atoms, and at least one aromatic ring, whereby 1 to 3 ring atoms can be selected from N and/or S and/or O;
G3 is selected from 
xe2x80x83whereby r and s as well as the substituents R13, R14 and R15 can have the above meanings, or the grouping
xe2x80x94NR13R15
xe2x80x83can also be nitrogen heterocycle bound over the nitrogen atom selected from saturated or unsaturated monocyclic, four to eight-heterocycles which, aside from the essential nitrogen atom, can optionally further contain one or two further hetero-atoms selected from N and/or S and/or O, or saturated or unsaturated bi- or tricyclic, anellated or bridged heterocycles with 8 to 16 ring atoms, which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from N and/or S and/or O;
G4 is selected from 
xe2x80x83whereby r and s as well as the substituents R13, R14 and R15 and optionally the group xe2x80x94NR13R15 can have the above meanings and
R16 is selected from hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, benzyl and phenyl;
R17 is selected from trifluoromethyl, C1-C6-alkoxy, C3-C6-alkenyloxy and benzyloxy; and whereby
Ar1 and Ar21 are selected independently from each other from phenyl, pyridyl or naphthyl;
G5 has the meaning
xe2x80x94Wxe2x80x94(CH2)rxe2x80x94(CR14R15)sxe2x80x94R13xe2x80x83xe2x80x83(G5a)
xe2x80x83or 
xe2x80x83whereby r and s as well as the substitutents R13, R14, R15, Ar1 and Ar2 can have the above meanings and
W is O or S,
whereby the ring systems xe2x95x90CR13R15, xe2x80x94NR13R15 and optionally ER13, R15 as well as aromatic ring systems in the substituents R1, R4, R5, R13, R14, R15, R16, R17, Ar1 and Ar2 can be substituted independently from each other by one to three of the same or different groups selected from halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-cycloalkyl, phenyl, benzyl, hydroxy, C1-C6-hydroxyalkyl, C1-C6-alkoxy, C1-C6-alkoxy entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, C1-C6-alkylthio, carboxy, C2-C7-carboxyalkyl, C2-C7-carboxyalkenyl, C2-C7-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C1-C6-alkylamino, di-(C1-C6-alkyl)amino and, for two adjacent residues on the aromatic ring, methylendioxy, and whereby
alkyl-, alkenyl- and cycloalkyl residues in the groups G1 to G5 can be substituted by one or two of the same or different groups selected from hydroxy, carboxy, C2-C7-alkoxycarbonyl benzyloxycarbonyl, amino, mono-C1-C6-alkylamino and di-(C1-C6-alkyl)amino;
the salts, isomers and tautomers of the above defined compounds as well as their mixtures.
According to a particularly preferred embodiment, the invention relates to compounds of the general Formula (1) 
wherein the substituents have the following meanings:
R1 is selected from hydrogen, halogen, cyano, methyl, ethyl, trifluoromethyl, hydroxy, C1-C4-alkoxy, benzyloxy, C1-C5-alkanoyloxy, methylthio, ethylthio, methoxycarbonyl, tert-butoxycarbonyl aminocarbonyl, carboxy, phenoxy, and phenylthio;
R2 is selected from hydrogen, halogen, trifluoromethyl, hydroxy;
R3 is selected from hydrogen, halogen;
R4 is selected from hydrogen, C1-C3-alkyl, allyl, hydroxy and C1-C3-alkoxy;
k is 0 or 1,
A is selected from C2-C6-alkylene, optionally substituted once or twice by C1-C3-alkyl, hydroxy or fluorine;
C2-C6-alkylene, in which a methylene unit is isosterically replaced by O, S. CO, or SO2, whereby, with the exception of CO, the isosteric substitution cannot be adjacent to the amide group,
C2-C6-alkenylene, optionally substituted once or twice by C1-C3 alkyl, hydroxy and/or fluorine;
C4-C6-alkadienylene, optionally substituted by C1-C3-alkyl or one or two fluorine atoms;
1,3,5-hexatrienylene, optionally substituted by fluorine;
D is selected from C2-C8-alkylene, optionally substituted once or twice by methyl or hydroxy;
C4-C8-alkenylene, optionally substituted once or twice by methyl or hydroxy;
C4-C8-alkinylene, optionally substituted once or twice by methyl or hydroxy; and
C2-C8-alkylene, C4-C8-alkenylene or C4-C8-alkinylene, in which one to three methylene units are isosterically replaced by O, S, NH, N(CH3) N(COCH3), N(SO2CH3), CO, SO or SO2;
E is selected from 
xe2x80x83whereby the heterocyclic ring can optionally have a double bond and
n and p can be, independent of each other, the number 0, 1, 2 or 3 with the proviso that n+pxe2x89xa63 and
q is 1 or 2;
R11 is selected from hydrogen, C1-C3-alkyl, hydroxymethyl, or carboxy, and
R12 is selected from hydrogen or an oxo group adjacent to a nitrogen atom
G is selected from G1, G2, G3, G4 or G5, whereby
G1 is
xe2x80x94(CH2)rxe2x80x94(CR14R15)sxe2x80x94R13xe2x80x83xe2x80x83(G1)
r is 0 to 2 as well as
s is 0 or 1,
R13 is selected from
hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl; benzyl, phenyl; benzocyclobutyl, indanyl, indenyl, oxoindanyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenylenyl, fluorenyl, oxofluorenyl, anthryl, dihydroanthryl, oxodihydroanthryl, dioxodihydroanthryl, phenanthryl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl, oxodihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl, or tetrahydrodibenzocyclooctenyl bound directly or over a methylene group;
furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, benzofuryl, dihydrobenzofurl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, isoindolinyl, oxoindolinyl, dioxoindolinyl, benzooxazolyl, oxobenzooxazolinyl, benzoisoxazolyl, oxobenzoisoxazolinyl, benzothiazolyl, oxobenzthiazolinyl, benzoisothiazolyl, oxobenzoisothiazolinyl, benzoimidazolyl, oxobenzoimidazolinyl, indazolyl, oxoindazolinyl, benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl, oxodihydrothiazolopyridyl, isothiazolopyridyl, imidazopyridyl, oxodihydroimidazopyridyl, pyrazolopyridyl, oxodihydropyrazolopyridyl, thienopyrimidinyl, chromanyl, chromanonyl, benzopyranyl, chromonyl, quinolyl, isoquinolinoyl, dihydroquinolinyl, oxodihydroquinolinyl, tetrahydroquinolinyl, oxotetrahydroquinolinyl, bernzodioxanyl, quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl, pyridoindolyl, acridinyl, oxodihydroacridinyl, phenanthridinyl, oxodihydrophenanthridinyl, dibenzoisoquinolinyl, oxodihydrodibenzoisoquinolinyl, phenothiazinyl, dihydrodibenzooxepinyl, oxodihydrodibenzooxepinyl, benzocycloheptathienyl, oxobenzocycloheptathienyl, dihydrothienobenzothiepinyl, oxodihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, oxodihydrodibenzothiepinyl, octahydrodibenzothiepinyl, dibenzoazepinyl, dihydrodibenzoazepinyl, oxodihydrodibenzoazepinyl, octahydrodibenzoazepinyl, benzocycloheptapyridyl, oxobenzocycloheptapyridyl, pyridobenzoazepinyl, dihydropyridobenzoazepinyl, oxodihydropyridobenzoazepinyl, dihydropyridobenzodiazepinyl, oxodihydropyridobenzodiazepinyl, dihydrodibenzooxazepinyl, dihydropyridobenzooxepinyl, dihydropyridobenzooxazepinyl, oxodihydropyridobenzooxazepinyl, dihydrodibenzothiazepinyl, oxodihydrodibenzothiazepinyl, dihydropyridobenzothiazepinyl or oxodihydropyridobenzothiazepinyl bound directly or over a methylene group;
R14 is synonymous with R13 but is selected independent thereof;
R15 is selected from
hydrogen, hydroxy, methyl, benzyl, phenyl; indanyl, indenyl, naphthyl, tetrahydronaphthyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, benzofuryl, benzothienyl, indolyl, indolinyl, benzooxazolyl, benzothiazolyl, benzoimidazolyl, chromanyl, quinolinyl or tetrahydroquinolinyl bound directly or over a methylene group;
G2 is
xe2x95x90(C)uR13R15xe2x80x83xe2x80x83(G2)
xe2x80x83whereby R13 and R15 have the above meaning and
u is 0 or 1, or the grouping
xe2x95x90CR13R15
bound to E by means of a double bond in the case that V=1 can also be a ring system bound over the carbon atom selected from
indanyl, tetrahydronaphthyl, fluoroenyl, dihydroanthryl, tetrahydrobenzocycloheptenyl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl; tetrahydroquinolinyl, dihydroacridinyl, dihydrodibenzooxepinyl, dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, dibenzoazepinyl, dihydrodibenzoazepinyl, benzocycloheptapyridinyl, dihydrobenzocycloheptapyridinyl, pyridobenzoazepinyl, dihydropyridobenzoazepinyl;
or the two germinal substituents R13 and R15 can, in the case that u=0, form a spirocycle ER13R15 together with the ring E selected from dioxaazaspirononane, dithioazaspirononane, oxadiazaspirononane, oxadiazaspriononandione, triazaspirononane, triazaspirononandione, diazaspriodecanone, diazaspirodecandione, dioxaazaspirodecane, dithiaazaspirodecane, oxadiazaspirodecane, triazaspriodecane, triazaspirodecanone, triazaspirodecandione, dioxaazaspiroundecane, dithiaazasprioundecane, oxadiazaspiroundecanone, triazaspiroundecanone, spiro[benzodioxol-pyrrolidine], spiro[benzodioxol-piperidine], spiro[benzodioxin-piperidine] or spiro [dihydrobenzooxazin-piperdine];
G3 is selected from 
xe2x80x83whereby r and s as well as the sustituents R13, R14 and R15 can have the above meanings or the grouping
xe2x80x94NR13R15
represents the ring bound over the nitrogen atom of the following ring systems;
pyrrolidine, piperidine, hexahydroazepine, octahydroazocine, piperazine, hexahydrodiazepine, morpholine, hexahydrooxazepine, thiomorpholine, thiomorpholin-1,1-dioxide, 2-azabicyclo[2.2.1]heptane, 7-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-azabicyclo[2.2.2]octane, 8-azabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane, indoline, isoindoline, (1H)-dihydroquinoline, (1H)-tetrahydroquinoline, (2H)-tetrahydroisoquinoline, (4H)-dihydrobenzooxazine, (4H)-dihydrobenzothiazine, (1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[c]azepine, (1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine, (5H)-tetrahydrobenzo[b]thiazepine, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, carbazole, (10H)-dihydroacridine, (10H)-dihydrophenanthridine, 1,2,3,4-tetrahydroacridanone, (10H)-phenoxazine, (10H)-phenothiazine, (5H)-dibenzoazepine, (5H)-dihydrodibenzoazepine, (5H)-octahydrodibenzoazepine, dihydrobenzo[d,e]isoquinoline, (5H)-dihydrodibenzodiazepine, (5H)-benzo[b]pyrido[f]azepine, (5H)-dihydrobenzo[b]pyrido[f]azepine, (11H)-dihydrodibenzo[b,e]oxazepine, (11H)-dihydrodibenzo[b,e]thiazepine, (10H)-dihydrodibenzo[b,f]oxazepine, (10)-dihydrodibenzo-[b,f]thiazepine, (5)-tetrahydrodibenzoazocine, (11H)-dihydrobenzo[e]pyrido[b]-1,4-diazepin-6-one or (11H)-dihydrobenzo[b]pyrido[e]-1,4-diazepin-5-one;
G4 is selected from 
xe2x80x83whereby r and s as well as the substituents R13, R14, R15 and optionally the grouping xe2x80x94NR13R15 can have the above meanings;
R16 is selected from hydrogen, C1-C6-alkyl, benzyl and phenyl;
R17 is selected from Trifluoromethyl, C1-C6-alkoxy, and benzyloxy, and
Ar1 and Ar2 are selected independent from each other from phenyl, pyridyl or naphthyl;
G5 is
xe2x80x94Wxe2x80x94(CH2)rxe2x80x94(CR14R15)sxe2x80x94R13xe2x80x83xe2x80x83(G5a)
xe2x80x83or 
xe2x80x83whereby r and s as well as the substituents R13, R14,R15, Ar1 and Ar2 can have the above meanings, and
W is O, and
the rings systems xe2x95x90CR13R15, xe2x80x94NR13R15 and optionally ER13, R15 as well as aromatic ring systems in the substituents R1, R13, R14, R15, R16, R17, Ar1 and Ar2 can be substituted independently from each other by one to three of the same or different groups selected from halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-cycloalkyl, phenyl, benzyl, hydroxy, C1-C6-hydroxyalkyl, C1-C6-alkoxy, C1-C6-alkoxy entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, C1-C6-alkylthio, carboxy, C2-C7-carboxyalkyl, C2-C7-carboxyalkenyl, C2-C7-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C1-C6-alkylamino, di-(C1-C6-alkyl)amino and, for two adjacent residues on the aromatic ring, methylenedioxy, and whereby alkyl-, alkenyl- and cycloalkyl residues in the groups G1 to G5 can be substituted by one or two of the same or different groups selected from hydroxy, carboxy, C2-C7-alkoxycarbonyl, benzyloxycarbonyl, amino, mono-C1-C6-alkylamino and di-(C1-C6-alkyl)-amino; the salts, isomers and tautomers of the above defined compounds as well as optionally their mixtures.
The invention especially relates to compounds of the general formula (I), 
according to claim 1, 2, 3 or 4, wherein the substituents have the following meanings:
R1 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, hydroxy, C1-C4-alkoxy, methylthio, ethlythio, carboxy and phenoxy;
R2 is selected from hydrogen, chlorine and methyl;
R3 is hydrogen;
R4 is selected from hydrogen, C1-C3-alkyl and hydroxy,
k is 0
A is selected from C2-C6-alkylene, which is optionally substituted once or twice by hydroxy or fluorine;
C2-C6-alkylene, wherein a methylene unit is isosterically replaced by O, S or CO, whereby, with the exception of CO, the isosteric substitution cannot be adjacent to the amide group;
C2-C6-alkenylene which is optionally substituted by C1-C3-alkyl and/or fluorine;
C4-C6-alkadienylene;
D is selected from C4-C8-alkylene which is optionally substituted by methyl or hydroxy;
C4-C8-alkenylene, which is optionally substituted by hydroxy;
C4-C8-alkinylene, which is optionally substituted by hydroxy;
C4-C8-alkylene, C4-C8-alkenylene, C4-C8-alkinylene wherein a methylene unit is respectively isosterically replaced by O, NH, N(CH3), CO or SO2 or an ethylene group is isosterically replaced by a group NHxe2x80x94CO and/or COxe2x80x94NH or a propylene group is isosterically replaced by a group NHxe2x80x94COxe2x80x94O and/or Oxe2x80x94COxe2x80x94NH;
E is selected from pyrrolidine, piperidine, hexahydroazepine or morpholine, wherein the ring can be optionally substituted by a methyene group and/or by an oxo group adjacent to a nitrogen atom;
G is selected from methoxycarbonylamino, ethoxycarbonylamino tert-butoxycarbonylamino, benzyloxycarbonylamino, trifluoroacetylamino, diphenylphosphinoylamino, diphenylphosphinoyloxy, diphenylmethyloxy, or a group 
xe2x80x83whereby
r is 0 or 1, and
s is 0 or 1, as well as
u is 0 or 1,
R13 is selected from hydrogen, methyl, benzyl, phenyl;
indanyl, indenyl, oxoindanyl, naphthyl, tetrahydronaphthyl, fluorenyl, anthryl, phenanthryl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl or oxodihydrodibenzocycloheptenyl;
thienyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzofuryl, benzothienyl, indolyl, indolinyl, isoindolinyl, oxoindolinyl, dioxoindolinyl, benzooxazolyl, oxobenzooxazolinyl, benzoisoxazolyl, oxobenzoisoxazolinyl, benzothiazolyl, oxobenzothiazolinyl, benzoisothiazolyl, oxobenzoisothiazolinyl, benzoimidazolyl, oxobenzoimidazolinyl, benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl, oxodihydrothiazolopyridyl, imidazopyridyl, oxodihydroimidazopyridyl, quinolyl, isochinolinyl, dihydroquinolinyl, oxodihydroquinolinyl, tetrahydroquinolinyl, oxotetrahydroquirclinyl, carbazolyl, tetrahydrocarbazolyl, pyridoindolyl, acridinyl, oxodihydroacridinyl, phenanthridinyl, dihydrophenanthridinyl, oxodihydrophenanthridinyl, dihydrobenzoisoquinolinyl, oxodihydrobenzoisoqu inolinyl, phenothiazinyl, dihydrodibenzooxepinyl, benzocycloheptathienyl, dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, dibenzoazepinyl, dihydrodibenzoazepinyl, oxodihydrodibenzoazepinyl, benzocycloheptapyridyl, oxodihydrobenzocycloheptapyridyl, pyridobenzoazepinyl, dihydropyridobenzoazepinyl, oxodihydropyridobenzoazepinyl, dihydropyridobenzodiazepinyl, oxodihydropyridobenzodiazepinyl, dihydrodibenzooxazepinyl, dihydropyridobenzooxazepinyl, dihydrodibenzothiazepinyl or dihydropyridobenzothiazepinyl;
R14 is selected from hydrogen, methyl, benzyl, phenyl;
R15 is selected from hydrogen, hydroxy, methyl, benzyl, phenyl, indanyl, inaenyl, naphthyl, tetrahydronaphthyl, furyl, thienyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzofuryl, benzothienyl, indolyl, indolinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, quinolinyl or tetrahydroquinolinyl;
R16 is selected from hydrogen, C1-C4-alkyl, benzyl and phenyl;
Ar1 and Ar2 are selected independent from each other from phenyl, pyridyl or naphthyl; and
the grouping xe2x95x90(C)uR13R15 is selected from
indanyl, tetrahydronaphthyl, fluorenyl, tetrahydrobenzocycloheptenyl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl;
tetrahydroquinolinyl, dihydrodibenzooxepinyl, dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, dibenzoazepinyl, dihydrodibenzoazepinyl, benzocycloheptapyridinyl, dihydrobenzocycloheptapyridinyl pyridobenzoazepinyl, dihydropyridobenzoazepinyl;
and the grouping ER13, R15 represents a spirocycle selected from dioxaazaspirodecane, dithiaazaspirodecane, diazaspirodecanone, diazaspirodecandione, triazaspirodecanone, triazaspiro-decandione, dioxaazaspiroundecane, dithiaazaspiroundecane, oxadiazaspiroundecanone, triazaspiroundecanone, spiro[benzo-dioxol-pyrrolidin], spiro[benzodioxol-piperidine], spiro-[benzodioxin-piperidine], spiro [dihydrobenzoxazin-piperi-dine];
and whereby the grouping xe2x80x94NR13R15 represents a ring of heterocycle bound over the nitrogen atom selected from the following: piperidine, hexahydroazepine, piperazine hexahydrodiazepine, morpholine, thiomorpholine, indoline, isoindoline, (1H)-dihydroquinoline, (1H)-tetrahydroquinoline, (2H)-tetrahydroisoquinoline, (4H)-dihydrobenzooxazine, (4H)-dihydrobenzothiazine, (1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[c]azepine, (1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydro-benzo[b]oxazepine, (5H)-tetrahydrobenzo[b]thiazepine, carbazole, (10H)-dihydroacridine, (10H)-dihydrophenanthridine, (5H)-dibenzoazepine, (5H)-dihydrodibenzoazepine, (5H)-dihydrodibenzodiazepine, (5H)-benzo[b]pyrido[f]azepine, (5H)-dihydrobenzo[b]pyrido[f]azepine, (11H)-dihydrodibenzo[b,e]oxazepine, (11H)-dihydrodibenzo[b,e]thiazepine, (10H)-dihydrodibenzo[b,f]oxazepine, (10H)-dihydrodibenzo[b,f]thiazepine, (11H)-dihydrobenzo[e]pyrido[b]-1,4-diazepin-6-one or (11H)-dihydrobenzo[b]pyrido[e]-1,4-diazepin-5-one,
xe2x80x83whereby the ring systems xe2x95x90CR13R15, xe2x80x94NR13R15 and optionally ER13, R15 as well as aromatic ring systems in the substituents R1, R13, R14, R15, R16, Ar1 and Ar2 can be substituted independently of each other by one to three of the same or different groups selected from halogen, cyano, C1-C6-Alkyl, trifluoromethyl, C3-C8-cycloalkyl, phenyl, benzyl, hydroxy, C1-C6-hydroxyalkyl, C1-C6-alkoxy, C1-C6-alkoxy entirely or partially substituted by benzyloxy, phenoxy, mercapto, C1-C6-alkylthio, carboxy, C2-C7-carboxyalkyl, C2-C7-carboxyalkenyl, C2-C7-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C1-C6-alkylamino, Di-(C1-C6-alkyl)-amino and, for two adjacent residues on the aromatic ring, methylenedioxy, and
xe2x80x83whereby alkyl-, alkenyl- and cycloalkyl residues in the groups G can be substituted by one or two of the same or different groups selected from hydroxy, carboxy, C2-C7-alkoxycarbonyl, benzyloxycarbonyl, amino, mono-C1-C6-alkylamino and di-(C1-C6-alkyl)-amino.
According to a further particular embodiment, the invention relates to new compounds of the general formula (I) 
R1 is selected from hydrogen, fluorine, methyl, trifluoromethyl ethylthio;
R2, R3 and R4 are each hydrogen;
k has the meaning 0,
A is selected from
ethylene, propylene or butylene optionally substituted by hydroxy or one or two fluorine atoms; or OCH2 or SCH2;
ethenylene, or 1,3-butadienylene;
D is selected from C4-C6-alkylene which is optionally substituted by hydroxy;
C4-C6 alkenylene;
C4-C6 alkinylene; or
C4-C6 alkylene, C4-C6 alkenylene or C4-C6 alkinylene, wherein one or two methylene units is isosterically replaced by O, NH, CO or SO2;
E is piperidine
G is selected from diphenylmethyl, diphenylhydroxymethyl, diphenylmethylene, naphthyl, tetrahydronaphthyl, tetrahydronaphthylidene, flqoroenyl, fluorenylidene, tetrahydrobenzocycloheptenyl or tetrahydrobenzocycloheptenylidene, dihydrodibenzoycloheptenyl or dihydrodibenzocycloheptenylidene;
mixed diphenyl;
phenyl-thienylmethyl, phenyl-thienylmethylene, phenyl-pyridylmethyl, phenyl-pyridylmethylene, tetrahydroquinolinyl, tetrahydroisoguinolinyl, benzocycloheptapyridinyl, benzocycloheptapyridinylidene, dihydrobenzocycloheptapyridinyl, dihydrobenzocycloheptapyridinylidene, dihydrodibenzooxepinyl, dihydrodibenzooxepinylidene, dihydrodibenzothiepinyl, Dihydrodibenzothiepinylidene, Dihydrobenzothienothiepinyl or dihydrobenzothienothiepinylidene;
indolyl, oxobenzoimidazolyl, oxobenzothiazolyl, benzoisothiazolyl or benzotriazolyl;
dibenzylaminocarbonyl, diphenylaminocarbonyl, indolinyl-N-carbonyl, isoindolinyl-N-carbonyl, tetrahydroquinolinyl-N-carbonyl, tetrahydrobenzoazepinyl-N-carbonyl, carbazolyl-N-carbonyl, dihydrodibenzoazepinyl-N-carbonyl or oxodihydrobenzopyridodiazepinyl-N-carbonyl;
diphenylmethylamino, diphenylmethyl-methylamino, dibenzylamino, benzylphenylamino or triphenylmethylamino; acetylamino, pivaloylamino, phenylacetylamino, diphenylacetylamino, diphenylpropionylamino, naphthylacetylamin, benzoylamino, benzoylmethylamino, naphthoylamino or oxofluorenylcarbonylamino;
furoylamino, pyridylacetylamino or pyridyicarbonylamino; benzylaminocarbonylamino, naphthylmethylaminocarbonylamino, indanylaminocarbonylamino, tetrahydronaphthylaminocarbonyl, dibenzylaminocarbonylamino, phenylylaminocarbonylamino, naphthylaminocarbonylamino, benzylphenylaminocarbonylamino or diphenylaminocarbonylamino;
indolinyl-N-carbonylamino, isoindolinyl-N-carbonylamino, tetrahydraquinolinyl-N-carbonylamino, tetrahydrobenzoazepinyl-N-carbonylamino, carbazolyl-N-carbonylamino, dihydrophenanthridinyl-N-carbonylamino, dihydrodibenzoazepin-N-carbonylamino, dihydrobenzopyridoazepinyl-N-carbonylamino or oxodihydrobenzopyridodiazepinyl-N-carbonylamino; methanesulfonylamino, tolylsulfonylamino, naphthylsulfonylamino or diphenylphosphinoylamino;
diphenylmethyloxy or diphenylphosphinoyloxy,
whereby aromatic ring systems can be substituted independently of each other by one to three of the same or different groups selected from halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-cycloalkyl, phenyl, benzyl, hydroxy, C1-C6-hydroxyalkyl, C1-C6-alkoxy, C1-C6-alkoxy entirely or partially substituted by fluorine, benzyl-oxy, phenoxy, mercapto, C1-C6-alkylthio, carboxy, C2-C7-carb-oxyalkyl, C2-C7-carboxyalkenyl, C2-C7-alkoxycarbonyl, benzyl-oxycarbonyl, nitro, amino, mono-C1-C6-alkylamino, di-(C1-C6-al-kyl)-amino and, for two adjacent residues on the aromatic ring, methylenedioxy, and whereby
alkyl-, alkenyl- and cycloalkyl residues in the group G can be substituted by one or two of the same or different groups selected from hydroxy, carboxy, C2-C7-alkoxycarbonyl, benzyloxycarbonyl, amino, mono-C1-C6-alkylamino and di-(C1-C6-alkyl)amino;
In the following, a series of compounds with the respective specific substituent definitions are listed in Table 1 without any limitation for further illustration of the compounds according to the invention.
Further subject-matter of the claims are analogous methods for the production of the compounds of formula (I) according to the invention.
According to method variant (A), compounds of formula (I) are obtained in the manner by reacting carboxylic acids of formula (II) 
in which R1, R2, R3, A and k have the meaning given above or their reactive derivatives with compounds of formula (III) 
wherein D, E, G and R4 are defined as above.
Reactive derivatives of compound (II) can be, for example, activated esters, anhydrides, acid halides (especially acid chlorides) or simple low alkyl esters. Suitable activated esters are, for example, p-nitrophenyl ester, 2,4,6-trichlorphenyl ester, pentachlorophenyl ester, cyanomethyl ester, esters of N-hydroxysuccinimide, N-hydroxyphthalimides, 1-hydroxybenzotriazole, N-hydroxypiperidine, 2-hydroxypyridine or 2-mercaptopyridine, etc.
Anhydrides can be symmetric anhydrides or mixed, as they are obtained, for example, with pivaloyl chloride or with chloroformates. Aromatic (for example chloroformic phenyl ester), araliphatic (for example chloroformic benzyl ester) or aliphatic chloroformates (for example chloroformic methyl ester, ethyl ester or isobutyl ester) can be used for this.
Reaction of the compounds of formula (II) with the compounds of formula (III) can also be carried out in the presence of candensation agents such as dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminpropyl)carbodiimide.hydrochloride, N,Nxe2x80x2-carbonyldiimidazole, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, etc. If carbodiimides are used as the condensation agent, reagents such as N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, N-hydroxypiperidine, etc. can be advantageously added.
Compounds of formula (III) can be used for reaction as free bases as well as in the form of their acid addition salts. For this, the salts of inorganic acids are to be preferred, i.e. hydrochlorides, hydrobromides or sulfates for example.
Reaction of compounds (II) or their reactive derivatives with compounds (III) are normally carried out in a suitable, preferably inert solvent. As examples, aromatic hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons (for example dichloromethane, chloroform, 1,2-dichloroethane, trichloroethylene), or ethers such as for example diethyl ether, tetrahydrofuran, dioxane, glycol dimethyl ether, ethyl acetate, acetonitrile or polar aprotic solvents such as, for example, dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone are to be named. Pure solvents, as well as mixtures of two or more, can be used.
The reaction is optionally carried out in the presence of an auxiliary base. Suitable examples for this are alkali metal carbonates such as sodium carbonate or potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate or potassium hydrogen carbonate or organic bases such as, for example, triethylamine, ethyl diisopropylamine, tributylamine, N-metbylmorpholine or pyridine. A suitable excess of the compound of formula (III) can also be used as a base. If compounds of formula (III) are used in form of their acid addition salts, then it is appropriate to consider the amount of auxiliary base used as equivalent.
The reaction temperatures canxe2x80x94depending on reactivity of the starting materialsxe2x80x94vary in a wide range. Generally, the reaction is carried out at temperatures between xe2x88x9240xc2x0 C. and 180xc2x0 C., preferably between xe2x88x9210xc2x0 C. and 130xc2x0 C., especially at the boiling point of the solvent used.
The starting compounds (II) and (III) are known and/or can be produced according to known methods in an analogous manner. Moreover, the production of representative examples is described below.
Additionally, compounds of formula (I) wherein G corresponds to the definitions G4a to G4e can also be produced according to the variant pursuant to Method B by reacting compounds of formula (I) wherein Gxe2x95x90NHR16, and which themselves represent active ingredients according to the invention with suitable alkylation or arylation agents and/or carboxylic acid, carboxaminic acid, sulfonic acid or phosphinic acid derivatives of the formula (IVa) to (IVe) 
wherein L signifies respectively a suitable nucleofuge. The type of nucleofuge L and the conditions of the reaction are dependent of the nature of the residue to be transferred.
By means of method variant (B1), compounds of formula (I), in which G, with the exception of NHR16, has the meaning of G4a according to the above definition can also be synthesized by reacting compounds of formula (I), in which G is NHR16, with a suitable alkylation agent and/or arylation agent of formula (IIVa), wherein r, s, R13, R14, and R15, are defined above and the leaving group L can be a reactive derivative of an alcohol, for example, a halogen atom such as chlorine, bromine or iodine or a sulfonic acid ester, i.e. for example a methanesulfonyloxy group, trifluoromethanesulfonyloxy-, ethanesulfonyloxy-, benzenesulfonyloxy-, p-toluenesulfonyloxy-, p-bromobenzenesulfonyloxy-, m-nitrobenzenesulfonyloxy group.
The reaction of compounds of formula (I), in which G is the residue NHP16 with the compounds of formula (IVa) is usually conducted in a suitably inert solvent. Such solvents can be for example the following: aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as for example tetrahydrofuran, dioxane, glycol dimethyl ether, ethyl acetate or acetonitrile, ketones such as acetone or ethyl methyl ketones, polar protic solvents such as alcohols for example ethanol, isopropanol or butanol or also glycol monomethyl ether; or polar aprotic solvents such as, for example, dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone. Pure solvents as well as mixtures of two or more can also be used.
Preferably, the reactions are carried out in the presence of bases, whereby the same bases as named in method variant (A) above can be used. If chlorides or bromides are used as the compound of formula (IVa), the reaction can be accelerated in this manner by the addition of alkali metal iodides such as sodium iodide or potassium iodide. The reaction temperatures can vary between 0xc2x0 C. and 180xc2x0 C. depending on the reactivity of the educts, but preferably lie between 20xc2x0 C. and 130xc2x0 C.
According to the method variant (B2), compounds of formula (I), in which G has the meaning of G4b to G4e according to the above definition, can also be produced by reacting compounds of formula (I), wherein G is the residue NHR16, with a carboxylic acid, carbamic acid, sulfonic acid and/or phosphinic acid of formula (Vb) to (Ve) wherein r, s, R13, R14, R15, Ar1, Ar2 and optionally the group NR13R15 have the present meanings, 
or their derivatives capable of reaction. Preferred derivatives of carboxylic acids according to formulas (Vb) and (Vc) and/or sulfonic acids of formula (Vd) which are capable of reaction are representatives of symmetric or unsymmetric carboxylic acid anhydrides and/or sulfonic acid anhydrides or carboxylic halides and/or sulfonyl halides, especially carboxylic and/or sulfonyl chlorides. Preferred derivatives of carbamates according to formula (Vc), wherein r=0, and/or phosphinic acids of formula (Ve) which are capable of reaction are the carbamoyl halides and/or phosphinyl halides, especially carbamyl- and/or phosphinyl chlorides. The reaction of the acids according to formula (V) and/or their reactive derivatives with compounds of formula (I), in which G is the residue NHR16, preferably occurs in the presence of auxiliary bases in solvents and under conditions as they are described in method variant (A).
Compounds of formula (I), wherein G represents a carbamoyl residue according to the definition (G4c) with r=0, i.e. a group 
can also be produced aside according to variants (A) and (B2), pursuant to the variant method (B3) by reacting compounds of formula (I), in which G represents the residue NHR16, with a carbonyl group transmitter to an intermediate product and subsequently reacting this directly with a primary or secondary amine with the formula (VI)
Hxe2x80x94NR13R15xe2x80x83xe2x80x83(VI)
wherein the residues R13 and R15 have the meanings according to the above definitions without purifying or isolating the intermediate product.
Bis-trichloromethyl carbonate (triphosgene) and carbonyldiimidazole have been proven as particularly reactive carbonyl group transmitters. The reaction of compounds of formula (I), wherein G is residue NHR16, with triphosgene and/or carbonyldiimidazole are typically conducted in an absolute, inert solvent in the presence of a tertiary organic amine as an auxiliary base in such a manner that the solution of compounds (I) and the auxiliary base are slowly poured into a solution of an equivalent amount of carbonyl group transmitter. Thereby, the reaction requires molar ratios of 1:1 for the reaction of compound (I) and carbonyldiimidazole, and, in contrast, a ratio of 1:0.35 for the use of triphosgene. After complete reaction of the components to the intermediate product, compound (VI) is added in stochiometric amounts or in excess as a solution or a solid and the reaction is typically completed at elevated temperature. Suitable inert solvents are, for example hydrocarbons such as hexane, heptane, benzene, toluene, xylene, chlorinated hydrocarbons such as for example dichloromethane, chloroform, 1,2-dichloroethane or trichloroethylene, ethers such as for example diethyl ether, tetrahydrofuran or dioxane, esters such as ethyl acetate, butyl acetate, acetonitrile; or polar aprodic solvents such as formamide or dimethylformamide. Pure solvents as well as mixtures of various solvents can be used. Amines such as for example triethylamine, ethyl diisopropylamine, tributylamine, N-methylmorpholine or pyridine are suitable as auxiliary bases.
If the compounds or formula (I) or formula (VI) are used as salts, the amount of the auxiliary base is increased accordingly. The reaction temperatures can lie between xe2x88x9240xc2x0 C. and 50xc2x0 C. for the first partial reaction, preferably 0xc2x0 C. to 30xc2x0 C., and between 0xc2x0 C. and 150xc2x0 C. for the second partial reaction, preferably 20xc2x0 C. to 120xc2x0 C.
According to method variant pursuant (B4), compounds of formula (I), wherein G represents a carbamoyl residue according to the definition (G4c) with r=0 and R15 hydrogen, i.e. the group 
can also be produced, aside according to variants (A), (B2) and (B3), by reacting the compounds of formula (I) in which G is the residue NHR16, with an isocyanate of formula (VII)
xe2x80x83Oxe2x95x90Cxe2x95x90Nxe2x80x94R13xe2x80x83xe2x80x83(VII).
in which R13 has the above defined meaning
Reaction of the compounds of formula (I), in which G is the residue NHR16, with the isocyanates of formula (VII) are conducted thereby in absolute, inert solvents as they are named above in method (B3). Mixtures of various solvents can also be used. Thereby, the reaction temperatures can vary in the region from xe2x88x9220xc2x0 C. to 150xc2x0 C., but preferably lie at 20xc2x0 C. to 100xc2x0 C.
As already mentioned, the compounds of formula (I), wherein G represents the residue NHR16, are themselves active ingredients according to the invention with tumor growth inhibiting activity. However, independent of their therapeutic applicability, they also represent useful intermediate compounds for the production of a multitude of other compounds according to the invention corresponding to the method variants (B1) to (B4).
In principle, they themselves, can be produced according to method A by reacting a carboxylic acid of formula (II) with amines of formula (III) in which G is the residue NHR16 as. described above. However, since the compounds of formula (III) with NHR16 as G represent xcex1, xcfx89-diamines, the formation of product mixtures is always to be expected in their reaction with carboxylic acids (II). In this case, this makes a subsequent separation necessary.
In contrast, compounds of formula (I), in which G is the residue NHR16, are essentially more advantageously produced from other compounds of formula (I), in which G, within the meaning of G4, is a selectively cleavable group under mild conditions which corresponds to a nitrogen protective group.
In this connection, among the compounds according to formula (I) with the named pharmacological properties, compounds in which the nitrogen atom of G4 carries, aside from the residue R16, G a benzyl group, a 4-methoxybenzyl group, a diphenylmethyl group, a triphenylmethyl group, a benzyloxy-carbonyl group, a methoxy- and/or ethoxycarbonyl group, a tert-butoxycarbonyl group, an allyloxycarbonyl group or a trifluoroacetyl group are particularly suitable. Thus, compounds of formula (I) with NR16-benzyl, NR16-diphenylmethyl, NR16-triphenylmethyl or NR16-benzyloxycarbonyl groups as G can already be catalytically transformed into compounds of formula (I) with NHR16 as G at room temperature under mild conditions with elementary hydrogen or by transfer hydration. Compounds of formula (I) with a NR16-(4-methoxybenzyl) group are converted to compounds of formula (I) with NHR16 as G by selective oxidation with ammonium-cer(IV)-nitrate. The cleavage of simple NR16-alkoxycarbonyl groups such as the methoxy - or ethoxycarbonyl group as well as the NR16-trifluoroacetyl group as G in compounds of formula (I) succeed by alkali hydrolysis under mild conditions without cleaving the A and D linked amide function. This is suitably valid for the cleavage of the NR16-triphenylmethyl group and the NR16-tert-butoxycarbonyl group as G in compounds of formula (I) which occurs in acidic medium under mild conditions. Finally, compounds of formula (I) with an NR16-allyloxycarbonyl group as G can be converted into such with NHR16 G in neutral medium with palladium catalyst.
All these methods are fully familiar to the person skilled in the art, and are furthermore also documented in various monographs, see for example Greene, Wuts: Protective Groups in Organic Synthesis, New York, 1991.
The compounds of formula (I) produced according to the methods (A) to (B) can be isolated and purified in a known manner, for example by subjecting the residue after distillation of the solvent to partition, extraction, re-precipitation or re-crystallization or another purification method. For this, column chromatography on a suitable support or preparative middle or high pressure liquid chromatography (HPLC) are preferred for this.
The compounds (I) are first normally obtained in form of their free bases or their hydrates or solvates, depending on the type of isolation and purification. Their addition salts with pharmaceutically suitable acids are obtained in a typical manner by converting the base with the desired acid in a suitable solvent. Depending on the number of basic centers of compounds (I), one or more equivalent acids per mole of base can be bound.
Suitable solvents are, for example, chlorinated hydrocarbons such as dichloromethane or chloroform; ethers such as diethyl ether, dioxane or tetrahydrofuran; acetonitrile; ketones such as acetone or ethyl methyl ketone; esters such as methyl acetate or ethyl acetate or low molecular alcohols such as methanol, ethanol or isopropanol; as well as water. Pure solvents as well as mixtures of two or three solvents can also be used. The salts can be isolated by crystallization, precipitation or the evaporation of the solvent. Thereby, they optionally accumulate as hydrates or solvates.
The bases can be recovered from the salts by alkalization, for example with aqueous ammonia solution, alkali carbonate or diluted sodium hydroxide solution.